2-Decarboxy-2-aminomethyl-6-keto-PGE1 compounds

ABSTRACT

Prostaglandin E (PGE)-type derivatives and analogs having a 6-keto feature are disclosed, including processes for preparing them and the appropriate intermediates, said derivatives having pharmacological activity. 
     DESCRIPTION

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of co-pending applicationSer. No. 829,679, filed Sept. 2, 1977, now U.S. Pat. No. 4,205,178,which is a continuation-in-part of Ser. No. 755,675, filed Dec. 30,1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-decarboxy-2-aminomethyl-6-keto-PGE₁ compounds which are useful agentsfor the induction of prostacyclin-like pharmacological effects.Accordingly, these compounds are useful for pharmacological purposes forwhich prostacyclin and related substances are employed. The essentialmaterial constituting disclosure of the preparation and use of thesenovel compounds is incorporated here by reference from Ser. No. 829,679,filed Sept. 2, 1977 now U.S. Pat. No. 4,205,178.

SUMMARY OF THE INVENTION

The present invention particularly provides a compound of the formula##STR1## wherein W₁ is α-OH:β-H, α-H:β-OH, α-H:β-H, methylene, or α-CH₂OH:β-H;

wherein Q is oxo, α-H:β-H, α-R₈ :β-OH, or α-OH:β-R₈,

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is

(1) --C(R₅)(R₆)--C_(g) H_(2g) --CH₃

(2) --C(R₅)(R₆)--Z--(Ph) or

(3) cis--CH₂ --CH═CH--CH₂ CH₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s,

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, and

wherein s is zero, one, 2 or 3, with the proviso that not more than twoT's are other than alkyl and when s is 2 or 3 the T's are either thesame or different;

wherein R_(g) is hydrogen, methyl or ethyl; and

wherein R₂₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive,aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with alkyl of one to 4 carbon atoms, inclusive;

wherein D is

(1) --(CH₂)_(d) --C(R₂)₂ --

(2) --CH₂ --O--CH₂ --Y-- or

(3) --CH₂ CH═CH--

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being thesame or different with the proviso that one R₂ is not methyl when theother is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

and wherein X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C.tbd.C--

(4) --CH₂ CH₂ --.

With regard to the divalent substituents described above, e.g., Q andW₁, these divalent radicals are defined as α-R_(i) :β-R_(j), where R_(i)represents a substituent of the divalent moiety of the alphaconfiguration with respect to the cyclopentane ring and R_(j) representsa substituent of the divalent moiety of the beta configuration withrespect to the cyclopentane ring. Accordingly, when Q is defined asα-OH:β-R₈, the hydroxy of the Q moiety is in the alpha configuration,i.e. as in prostacyclin, and the R₈ substituent is in the betaconfiguration. Not all carbon atoms to which such divalent moieties areattached represent asymmetric centers. For example, when both valencebonds are to hydrogen (e.g., W₁ or Q is α-H:β-H), then no asymmetriccenter is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemicalcompounds:

2-decarboxy-2-aminomethyl-6,15-diketo-PGE₁ ;

2-decarboxy-2-aminomethyl-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-16,16-dimethyl-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-16-phenyl-17,18,19,20-tetranor-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-15(S)-15-methyl-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-(15R)-15-methyl-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-6-keto-13,14-didehydro-PGE₁ ;

2-decarboxy-2-aminomethyl-6-keto-13,14-didehydro-(15R)-PGE₁ ;

2-decarboxy-2-aminomethyl-6-keto-13,14-dihydro-PGE₁ ;

2-decarboxy-2-aminomethyl-2,2-difluoro-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-2,2-difluoro-16,16-dimethyl-6keto-PGE₁ ;

2-decarboxy-2-aminomethyl-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁;

2-decarboxy-2-aminomethyl-2,2-difluoro-(15S)-15-methyl-6-keto-PGE₁ ;

2-decarboxy-2-aminomethyl-2,2-difluoro-13,14-didehydro-6-keto-PGE₁ ; and

2-decarboxy-2-aminomethyl-2,2-difluoro-13,14-dihyrdo-6-keto-PGE₁.

I claim:
 1. A compound of the formula ##STR2## wherein W₁ is a α-OH:β-H,α-H:β-OH, α-H:β-H, methylene, or α-CH₂ OH:β-H;wherein Q is oxo, α-H:β-H,α-R₈ :β-OH, or α-OH:β-R₈ wherein R₈ is hydrogen or alkyl of one to 4carbon atoms, inclusive; wherein R₄ is(1) --C(R₅)(R₆)--C_(g) H_(2g)--CH₃ (2) --C(R₅)(R₆)--Z--(Ph) or (3) cis--CH₂ --CH═CH--CH₂ CH₃, whereinC_(g) H₂ g is alkylene of one to 9 carbon atoms, inclusive, with one to5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminalmethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro andthe further proviso that neither R₅ nor R₆ is fluoro when Z is oxa(--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j)wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbonatoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆-- and the (Ph); wherein (Ph) is phenyl or phenyl substituted by (T)s,wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, and wherein s is zero, one, 2 or 3, with the provisothat not more than two T's are other than alkyl and when s is 2 or 3 theT's are either the same or different; wherein R₉ is hydrogen, methyl orethyl; and wherein R₂₈ is hydrogen, alkyl of one to 4 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl or phenylsubstituted with alkyl of one to 4 carbon atoms, inclusive; wherein Dis(1) --(CH₂)_(d) --C(R₂)₂ -- (2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂--CH═CH-- wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro,being the same or different with the proviso that one R₂ is not methylwhen the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂--, and wherein X is(1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C--(4) --CH₂ CH₂ --.
 2. A compound according to claim 1 wherein W₁ isα-OH:β-H.
 3. A compound according to claim 2 wherein D is --(CH₂)_(d)--C(R₂)₂ -- wherein d and R₂ are as defined in claim
 1. 4. A compoundaccording to claim 3 wherein D is --(CH₂)₃ --.
 5. A compound accordingto claim 4 wherein X is trans--CH═CH--.
 6. A compound according to claim5 wherein Q is oxo.
 7. 2-Decarboxy-2-aminomethyl-6,15-diketo-PGE₁, acompound according to claim
 6. 8. A compound according to claim 5wherein Q is α-OH:β-R₈, wherein R₈ is hydrogen, methyl or ethyl.
 9. Acompound according to claim 8 wherein R₈ is hydrogen. 10.2-Decarboxy-2-aminomethyl-6-Keto-PGE₁, a compound according to claim 9.11. 2-Decarboxy-2-aminomethyl-,16,16-dimethyl-6-keto-PGE₁, a compoundaccording to claim
 9. 12.2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁, acompound according to claim
 10. 13.2-Decarboxy-2-aminomethyl-16-phenyl-17,18,19,20- tetranor-6-keto-PGE₁, acompound according to claim
 10. 14.2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-6-keto-PGE₁, acompound according to claim
 10. 15. A compound according to claim 8wherein R₈ is methyl. 16.2-Decarboxy-2-aminomethyl-15(S)-15-methyl-6-keto-PGE₁, a compoundaccording to claim
 15. 17. A compound according to claim 5 wherein Q isα-R₈ :β-OH, wherein R₈ is hydrogen, methyl or ethyl. 18.2-Decarboxy-2-aminomethyl-(15R)-15-methyl-6keto-PGE₁, a compoundaccording to claim
 17. 19. A compound according to claim 4 wherein X is--C.tbd.C--.
 20. A compound according to claim 19 wherein Q isα-OH:β-R₈, wherein R₈ is hydrogen, methyl or ethyl. 21.2-Decarboxy-2-aminomethyl-6-keto-13,14-didehydro- PGE₁, a compoundaccording to claim
 20. 22. A compound according to claim 19 wherein Q isα-R₈ :β-OH wherein R₈ is hydrogen, methyl or ethyl. 23.2-Decarboxy-2-aminomethyl-6-keto-13,14-didehydro-(15R)-PGE₁, a compoundaccording to claim
 22. 24. A compound according to claim 4 wherein X is--CH₂ CH₂ --.
 25. 2-Decarboxy-2-aminomethyl-6-keto-13,14-dihydro-PGE₁, acompound according to claim
 24. 26. A compound according to claim 3wherein D is --(CH₂)₂ --CF₂ --.
 27. A compound according to claim 26wherein X is trans--CH═CH--.
 28. A compound according to claim 27wherein Q is α-OH:β-H. 29.2-Decarboxy-2-aminomethyl-2,2-difluoro-6-keto-PGE₁, a compound accordingto claim
 28. 30. 2-Decarboxy-2-aminomethyl-2,2-difluoro-16,16-dimethyl6-keto-PGE₁, a compound according to claim
 28. 31.2-Decarboxy-2-aminomethyl-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁,a compound according to claim
 28. 32. A compound according to claim 27wherein Q is α-OH:β-CH₃. 33.2-Decarboxy-2-aminomethyl-2,2-difluoro-(15S)-15-methyl-6-keto-PGE₁, acompound according to claim
 32. 34. A compound according to claim 26wherein X is --C.tbd.C--. 35.2-Decarboxy-2-aminomethyl-2,2-difluoro-13,14-didehydro-6-keto-PGE₁, acompound according to claim
 34. 36. A compound according to claim 26wherein X is --CH₂ CH₂ --. 37.2-Decarboxy-2-aminomethyl-2,2-difluoro-13,14-dihydro-6-keto-PGE1, acompound according to claim 36.